Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial.

BACKGROUND: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. PATIENTS AND METHODS: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. CONCLUSIONS: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

Infrared Reflection-Absorption Spectroscopy of α-Keto Acids at the Air-Water Interface: Effects of Chain Length and Headgroup on Environmentally Relevant Surfactant Films.

A variety of organic surfactants are found at air-water interfaces in natural environments, including on the surfaces of aqueous aerosols. The structure and morphology of these organic films can have profound impacts on material transfer between the gas and condensed phases, the optical properties of atmospheric aerosol, and chemical processing at air-water interfaces. Combined, these effects can have significant impacts on climate via radiative forcing, but our understanding of organic films at air-water interfaces is incomplete. Here, we examine the impact of the polar headgroup and alkyl tail length on the structure and morphology of organic monolayers at the air-water interfaces. First, we focus on the substituted carboxylic acids, α-keto acids, using Langmuir isotherms and infrared reflection absorption spectroscopy (IR-RAS) to elucidate key structures and phase behaviors of α-keto acids with a range of surface activities. We show that the structure of α-keto acids, both soluble and insoluble, at water surfaces is a compromise between van der Waals interactions of the hydrocarbon tail and hydrogen bonding interactions involving the polar headgroup. Then, we use this new data set regarding α-keto acid films at water surfaces to examine the role of the polar headgroup on organic films using a similar substituted carboxylic acid (α-hydroxystearic acid), an unsubstituted carboxylic acid (stearic acid), and an alcohol (stearyl alcohol). We show that the polar headgroup and its hydrogen bonding interactions can significantly affect the orientation of amphiphiles at air-water interfaces. Here, we provide side-by-side comparisons of Langmuir isotherms and IR-RA spectra for a set of environmentally relevant organic amphiphiles with a range of alkyl tail lengths and polar headgroup structures.

Landscape distribution and abundance of animal-associated adult filth flies on commercial swine facilities in North Carolina, US.

Filth flies associated with animal production transmit pathogens to humans and animals, propagate antimicrobial resistance in microbial communities and provoke nuisance litigation. Although dispersal of flies from facilities is often responsible for these negative effects, filth fly research on swine facilities has been limited to within the barns. Filth fly adaptations in space and time, as well as influences of abiotic and biotic factors impact distribution and abundance of animal-associated filth flies on swine production facilities. In this study, fly surveillance was conducted around four swine facilities in Bladen County, North Carolina, U.S.A. from January 2019 to October 2019. Traps were replaced weekly and animal-associated filth flies were identified. Flies were grouped for comparison based on biology and differences in pest management strategies. There were distinct differences in abundance and spatial distribution of different filth fly groups on the swine facilities, which are likely linked to environmental factors like spatial relation to crop production and species phenology. The impact of the observed temporal and spatial distribution and abundance is discussed in the context of filth fly management.

Profiling motives behind hedonic eating. Preliminary validation of the Palatable Eating Motives Scale.

The purpose of this study was to validate a new scale designed to measure individual motives for eating tasty foods and determine if any specific motive(s) are associated with obesity. The "Palatable Eating Motives Scale" (PEMS) is a self-report measure adapted from the Drinking Motives Questionnaire Revised (DMQ-R). N=150 racially-diverse college students (mean age: 24.4, BMI: 16-51kg/m(2)) were administered the PEMS along with the Binge-Eating Scale (BES) and the Yale Food Addiction Scale (YFAS) to test for convergent and incremental validity and the Sensitivity to Punishment and Reward Questionnaire (SPSRQ) for discriminant validity. The PEMS identified four motives for eating tasty food, the same ones found with the DMQ-R for alcohol intake: Social, Conformity, Enhancement, and Coping motives. The scales had good convergent validity with BES and YFAS scores but discriminated from the broader motivational constructs of inhibition and activation measured by the SPSRQ. Of the PEMS motives, Coping (eating tasty food to deal with problems and negative feelings) accounted for unique variance in BMI, and added to variance in BMI contributed by BES scores, showing incremental validity. YFAS scores did not contribute to BMI after controlling for binge-eating. Coping subscale scores were also significantly higher (p<0.001) among the severely obese (BMI>40). Motives behind palatable food intake are not homogenous and should be considered in personalized weight-loss strategies in future studies. In normal weight individuals, knowing one's dominant motive for eating tasty foods may help promote healthier food choices in times and places where they are most vulnerable to do otherwise.

Motives for eating tasty foods associated with binge-eating. Results from a student and a weight-loss seeking population.

The aim of this study was to use the Palatable Eating Motives Scale (PEMS) to determine if and what motives for eating tasty foods (e.g., junk food, fast food, and desserts) are associated with binge-eating in two diverse populations. BMI and scores on the PEMS, Yale Food Addiction Scale (YFAS), and Binge-eating Scale (BES) were obtained from 247 undergraduates at the University of Alabama at Birmingham (UAB) and 249 weight-loss seeking patients at the UAB EatRight program. Regression analyses revealed that eating tasty foods to forget worries and problems and help alleviate negative feelings (i.e., the 4-item Coping motive) was associated with binge-eating independently of any variance in BES scores due to sex, age, ethnicity, BMI, other PEMS motives, and YFAS scores in both students (R² = .57) and patients (R² = .55). Coping also was associated with higher BMI in students (p < 0.01), and in patients despite their truncated BMI range (p < 0.05). Among students, the motives Conformity and Reward Enhancement were also independently associated with binge-eating. For this younger sample with a greater range of BES scores, eating for these motives, but not for Social ones, may indicate early maladaptive eating habits that could later develop into disorders characterized by binge-eating if predisposing factors are present. Thus, identifying one's tasty food motive or motives can potentially be used to thwart the development of BED and obesity, especially if the motive is Coping. Identifying one's PEMS motives should also help personalize conventional treatments for binge-eating and obesity toward improved outcomes.

Effects of Ground Transport in Kemp's Ridley (Lepidochelys kempii) and Loggerhead (Caretta caretta) Turtles.

Many juvenile Kemp's ridley (Lepidochelys kempii) and loggerhead (Caretta caretta) turtles strand during fall on the beaches of Cape Cod (MA, USA), with total stranding numbers sometimes exceeding 300 turtles per year. Once rehabilitated, turtles must be released at beaches with appropriate water temperatures, often requiring transportation to southeastern coastal states of the USA. These transportation events (transports) may approach or exceed 24 h in duration. Kemp's ridley turtles are known to exhibit an adrenal stress response during such transports, but the effect of transport duration has been unclear, and no other sea turtle species has been investigated. To assess whether transport duration and/or species affects physiological reactions to transport, we studied pre- and post-transport physiological measures in Kemp's ridley and loggerhead turtles transported by ground for <6, ∼12, ∼18, or ∼24 h, comparing with matched "control events" in which turtles were studied without transport. Blood samples were analyzed for four stress-associated measures (corticosterone, glucose, total white blood cell [WBC] count, and heterophil/lymphocyte ratio [H/L]) and nine measures of clinical status (pH, pO2, pCO2, HCO3, sodium, potassium, ionized calcium, lactate, and hematocrit). In both species, stress-associated measures elevated significantly during transport, while handling without transport had no significant effects. Loggerheads exhibited a greater stress response than Kemp's ridleys across all transport durations. These results indicate that sea turtles do react physiologically to ground transport; therefore, minimizing transport time and streamlining transport logistics (where feasible) may help ensure release of rehabilitated turtles to sea in the best possible condition. Nonetheless, both species remained in good clinical condition even after 24 h transport, indicating that current transport protocols are generally safe for sea turtles from a clinical perspective.

Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.

Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the foraging gene (for), a gene that has two naturally occurring variants in Drosophila melanogaster food-search behavior: rover and sitter. Molecular mapping placed for mutations in the dg2 gene, which encodes a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Rovers had higher PKG activity than sitters, and transgenic sitters expressing a dg2 complementary DNA from rover showed transformation of behavior to rover. Thus, PKG levels affected food-search behavior, and natural variation in PKG activity accounted for a behavioral polymorphism.

Tri-trophic effects of transgenic insect-resistant tobacco expressing a protease inhibitor or a biotin-binding protein on adults of the predatory carabid beetle Ctenognathus novaezelandiae.

Tri-trophic impacts on adult predatory carabid beetles, Ctenognathus novaezelandiae, of insect-resistant transgenic tobacco plants expressing a serine protease inhibitor, bovine spleen trypsin inhibitor (BSTI), or a biotin-binding protein, avidin, were investigated. Both proteins could potentially affect this beetle, since avidin is known to be insecticidal to many beetle species and C. novaezelandiae midguts were shown to contain high levels of trypsin, a protease powerfully inhibited by bovine pancreatic trypsin inhibitor (a BSTI homologue) in vitro. Newly emerged field-collected adult C. novaezelandiae were fed exclusively for 280 days on Spodoptera litura larvae raised either on non-transgenic control, transgenic avidin (55 ppm) or transgenic BSTI (68 ppm) tobacco. Despite this long-term exclusive diet, there was no treatment effect on survival or fecundity and only minor and transient effects on beetles were observed. Data pooled across time and genders showed control-prey-fed beetles weighed 3% more than BSTI-prey-fed beetles and avidin-prey-fed beetles consumed 3-4% fewer prey than control- or BSTI-prey-fed individuals. Females in all treatments gained more mass and survived longer than males. Low exposure to the proteins because of dilution and deactivation within the prey is the most likely explanation for the lack of tri-trophic effects observed. Aditionally, the presence of a digestive chymotrypsin only partially inhibited by BSTI may provide an alternative path for proteolysis.

The Biomolecular Interaction Network Database and related tools 2005 update.

The Biomolecular Interaction Network Database (BIND) (http://bind.ca) archives biomolecular interaction, reaction, complex and pathway information. Our aim is to curate the details about molecular interactions that arise from published experimental research and to provide this information, as well as tools to enable data analysis, freely to researchers worldwide. BIND data are curated into a comprehensive machine-readable archive of computable information and provides users with methods to discover interactions and molecular mechanisms. BIND has worked to develop new methods for visualization that amplify the underlying annotation of genes and proteins to facilitate the study of molecular interaction networks. BIND has maintained an open database policy since its inception in 1999. Data growth has proceeded at a tremendous rate, approaching over 100 000 records. New services provided include a new BIND Query and Submission interface, a Standard Object Access Protocol service and the Small Molecule Interaction Database (http://smid.blueprint.org) that allows users to determine probable small molecule binding sites of new sequences and examine conserved binding residues.

Determinants of adherence to lifestyle intervention in adults with obesity: a systematic review.

Lifestyle intervention programmes are efficacious in the management of obesity but often report poor attendance and adherence rates that hinder treatment effectiveness and health outcomes. The aim of this systematic review is to identify (i) barriers to behaviour change and (ii) predictors of adherence to lifestyle intervention programmes in adults with obesity. Studies were identified by systematically reviewing the literature within Medline, PsycINFO, CINAHL, SPORTDiscus and Web of Science from inception to August 2016. Barriers to behaviour change include poor motivation; environmental, societal and social pressures; lack of time; health and physical limitations; negative thoughts/moods; socioeconomic constraints; gaps in knowledge/awareness; and lack of enjoyment of exercise. The most prominent predictors of adherence include early weight loss success, lower baseline body mass index (BMI), better baseline mood, being male and older age. The findings within this review provide novel insight to clinicians working in obesity and have important implications for lifestyle intervention programme design. Barriers to behaviour change need to be addressed early in treatment, with lifestyle intervention individualized accordingly. Predictors of adherence should also be taken into careful consideration, with negative moods and unrealistic weight loss expectations discussed at the outset. If adherence is improved, treatment effectiveness, health outcomes and the ultimate burden of chronic diseases could also be improved.

Behavioural treatment strategies improve adherence to lifestyle intervention programmes in adults with obesity: a systematic review and meta-analysis.

Poor adherence to lifestyle intervention remains a key factor hindering treatment effectiveness and health outcomes for adults with obesity. The aim of this systematic review and meta-analysis is to determine if behavioural treatment strategies (e.g. goal setting, motivational interviewing, relapse prevention, cognitive restructuring etc.) improve adherence to lifestyle intervention programmes in adults with obesity. Randomized controlled trials that investigated the use of behavioural treatment strategies in obesity management were identified by systematically reviewing the literature within Medline, PsycINFO, CINAHL, SPORTDiscus and Web of Science from their inception to August 2016. This meta-analysis shows that behavioural treatment interventions have a significant positive effect on session attendance (percentage) and physical activity (total min/week) in adults with obesity (M = 17.63 (95% confidence interval (CI) = 10.77, 24.50), z =5.0337, P < 0.0001 and M = 105.98 (95% CI = 58.64, 153.32), z =4.3878, P < 0.0001, respectively). This meta-analysis of randomized controlled trials provides evidence that behavioural treatment strategies improve adherence to lifestyle intervention programmes in adults with obesity. These strategies should be routinely incorporated into lifestyle intervention, obesity management and weight loss programmes with the aim of improving engagement and adherence. If adherence were improved, treatment effectiveness, health outcomes and the ultimate burden of chronic disease could also be improved.

Pathways to diabetic limb amputation. Basis for prevention.

We defined the causal pathways responsible for 80 consecutive initial lower-extremity amputations to an extremity in diabetic patients at the Seattle Veterans Affairs Medical Center over a 30-mo interval from 1984 to 1987. Causal pathways, either unitary or composed of various combinations of seven potential causes (i.e., ischemia, infection, neuropathy, faulty wound healing, minor trauma, cutaneous ulceration, gangrene), were determined empirically after a synthesis by the investigators of various objective and subjective data. Estimates of the proportion of amputations that could be ascribed to each component cause were calculated. Twenty-three unique causal pathways to diabetic limb amputation were identified. Eight frequent constellations of component causes resulted in 73% of the amputations. Most pathways were composed of multiple causes, with only critical ischemia from acute arterial occlusions responsible for amputations as a singular cause. The causal sequence of minor trauma, cutaneous ulceration, and wound-healing failure applied to 72% of the amputations, often with the additional association of infection and gangrene. We specified precise criteria in the definition of causal pathway to permit estimation of the cumulative proportion of amputations due to various causes. Forty-six percent of the amputations were attributed to ischemia, 59% to infection, 61% to neuropathy, 81% to faulty wound healing, 84% to ulceration, 55% to gangrene, and 81% to initial minor trauma. An identifiable and potentially preventable pivotal event, in most cases an episode involving minor trauma that caused cutaneous injury, preceded 69 to 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.

The longitudinal course of psychopathology in Cushing's syndrome after correction of hypercortisolism.

Endogenous Cushing's syndrome (CS) is associated with significant psychopathology during the course of the disease. The purpose of this study was to evaluate the psychological and endocrine status of patients with CS after correction of their hypercortisolism. Thirty-three patients with active CS were examined before and at 3 months (28 patients), 6 months (25 patients), and 12 months (29 patients) after correction of hypercortisolism. Before cure, 66.7% of the patients had significant psychopathology, with the predominant diagnosis of atypical depressive disorder (AD) in 51.5% and/or major affective disorder in 12%. After cure, overall psychopathology decreased significantly to 53.6% at 3 months, 36% at 6 months, and 24.1% at 12 months, when there was a parallel recovery of the hypothalamic-pituitary-adrenal axis assessed by serial morning ACTH stimulation tests. There was an inverse correlation between psychological recovery and baseline morning cortisol, but no correlation with ACTH-stimulated cortisol values at 60 min. AD continued to be the prevailing diagnosis after correction of hypercortisolism, whereas the frequency of suicidal ideation and panic increased. The presence of AD before and after correction of hypercortisolism might be due to glucocorticoid-induced suppression of hypothalamic CRH secretion. The slight increase in the incidence of panic after correction of hypercortisolism might be due to a decreased glucocorticoid restraint at the central arousal/sympathetic catecholaminergic system. We conclude that CS is associated with AD symptomatology, which gradually improves with time after correction of hypercortisolism. Health care providers should be aware of changes in symptomatology, including suicidal ideation and panic attacks, that occur in a subgroup of patients.

Sotalol kinetics in renal insufficiency.

Kinetics of sotalol, a beta adrenoceptor blocker, was studied in 20 patients with varying renal function. In subjects with creatinine clearance (Clcr) greater than or equal to 39 ml/min/m2, sotalol plasma clearance (x +/- SD) was 71 +/- 31 ml/min/m2, elimination half-life (t 1/2) was 8.1 +/- 3.4 hr, and renal clearance was 46 +/- 26 ml/min/m2. In patients with moderate renal impairment (Clcr = 8 to 38 ml/min/m2) elimination t 1/2 rose to 24.2 +/- 7.5 hr, and plasma clearance fell to 24 +/- 7 ml/min/m2. In patients receiving dialysis, elimination t 1/2 rose to 33.9 +/- 27.1 hr. Elimination t 1/2 during hemodialysis was 5.8 +/- 2.1 hr and was associated with a 56.7 +/- 21% reduction in plasma levels.

Aluminum absorption and excretion following sucralfate therapy in chronic renal insufficiency.

PURPOSE: To measure serum aluminum levels and urinary aluminum excretion in patients with chronic renal insufficiency (CRF) receiving therapeutic doses of sucralfate. PATIENTS: Six patients with CRF were enrolled in the study. Creatinine clearances ranged from 0.2 to 0.9 mL/second (mean +/- SD 0.40 +/- 0.25 mL/second). Seven subjects with normal renal function were also studied. METHODS: Each subject received sucralfate 1 g four times daily for 21 days. Serum and urine samples (serum only) were collected on baseline and on Days 2, (3), 8, 15, 22, (23, 24), 29, and 36. Samples were assayed by graphite furnace atomic absorption spectrophotometry. RESULTS: In CRF, serum aluminum levels (mumol/L) increased by Day 2 and remained elevated to Day 24. Urinary aluminum excretion (mumol/day) was elevated throughout the study. The elimination half-life of serum aluminum after therapeutic dosing of sucralfate was 13.1 +/- 3.1 days. In subjects with normal renal function, baseline serum aluminum levels were similar to those in CRF (0.12 +/- 0.12 versus 0.11 +/- 0.12 mumol/L), but serum aluminum levels were higher at the end of the study in CRF (Day 22, 0.24 +/- 0.17 versus 0.83 +/- 0.48 mumol/L). CONCLUSIONS: After therapeutic doses of sucralfate, significant elevations of serum aluminum levels occurred in CRF. Serum aluminum levels were higher in patients with CRF than in normal subjects. Long courses of sucralfate should be used with caution or avoided in CRF.

Synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one , a monoimine quinone with selective cytotoxicity toward cancer cells.

A regio and stereospecific synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one (1) was achieved by using titanium tetrachloride in methylene chloride in the preparation of the imine. The regiochemistry was assigned by single-crystal X-ray analysis. In vitro tests showed that this diastereomer is selectively active for some solid cancer tumors.

Molecular similarity from atomic electrostatic multipole comparisons. Application to anti-HIV drugs.

A procedure is presented for the rapid calculation of the similarity between a pair of molecules based on atomic electrostatic multipole comparison. The multipoles are derived from semiempirical SCF wave functions, and the results obtained compare favorably with ab initio results. The method is illustrated by correlating the similarity and anti-HIV-1 activity of a series of azo compounds. Some generalizations are presented on the structure-activity relationships which are based on the atomic multipole distribution in the azo compounds.

Concentration of radiolabeled cholesterol in a feminizing adenoma of the testis.

Quantitative tissue studies demonstrated increased 19-[131I]-iodocholesterol concentration in a feminizing adenoma of the testis. The potential application of iodocholesterol and its isomers in the detection of steroid-secreting neoplasms of the testis and ovary is suggested.

Clinical pharmacokinetics of propafenone.

Propafenone is a class 1C antiarrhythmic agent which is administered as a racemate of S(+)- and R(-)-enantiomers. It is well absorbed and is predominantly bound to alpha 1-acid glycoprotein in the plasma. The enantiomers display stereoselective disposition characteristics, the R-enantiomer being cleared more quickly. The hepatic metabolism of propafenone is polymorphic and genetically determined: about 10% of Caucasians have a reduced capacity to hydroxylate the drug. This polymorphic metabolism accounts for the marked interindividual variability in the relationships between dose and concentration, and between concentration and pharmacodynamic effects. During long term administration, the metabolism is saturable in patients with the 'extensive metaboliser' phenotype, leading to accumulation of the parent compound. Propafenone blocks fast inward sodium channels in a frequency-dependent manner, and also has moderate beta-blocking effects. Both the enantiomers and the 5-OH metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Propafenone typically slows conduction markedly but only modestly prolongs refractoriness. These cardiac effects are determined by the extent of its myocardial accumulation. The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias. Significant interactions occur when propafenone is coadministered with other drugs. It increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Doses of these drugs should therefore be decreased if they are coadministered with propafenone.

Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter.

The high prevalence of cardiovascular disease (CVD) in patients with kidney disease is well described. This Canadian, multicenter, observational cohort study reports the prevalence and risk factors of CVD associated with kidney disease, in a cohort of patients with established chronic kidney disease (CKD), who are followed-up by nephrologists. This analysis sought to answer 2 questions: (1) in patients with established CKD, are the prevalence and progression of CVD accounted for by conventional or uremia-related risk factors, and (2) to what extent can progression to renal replacement therapy (RRT) be explained by CVD versus traditional risk factors for kidney disease? This study population consists of 313 patients (predominantly men) who had a mean age of 56 years and a mean creatinine clearance of 36 mL/min. Thirty percent were diabetic. The overall prevalence of CVD was 46%, and was independent of severity of kidney dysfunction (P = 0.700). The median follow-up time was 23 months, for a total of 462 patient years. We note the overall incidence of CVD events (new CVD or worsening of CVD) was 47/244 (20%). The best predictors of new CVD events among those without preexisting CVD were diabetes (odds ratio [OR] = 5.35, P = 0.018) and age (OR = 1.26, P = 0.08). In those with preexisting CVD, low diastolic pressure (DP) (OR =.72, P = 0.004) and high triglycerides (OR = 1.48, P = 0.019) at baseline were independent predictors of progression of CVD. We could not determine an independent impact of kidney function on CVD in the overall cohort. Furthermore, we determined that the presence of CVD itself confers an increased risk for progression to RRT (relative risk [RR] = 1.58, P = 0.047), adjusted for kidney function. This is the first in-depth analysis of CVD in a cohort of patients with established chronic kidney disease who are not on dialysis. The question regarding the impact of the altered biology of uremia in contributing to CVD progression remains unanswered, and clearly needs further study. However, the findings do raise the issue of whether aggressive treatment of CVD and risk factors might, in fact, reduce progression to RRT. Further large-scale, observational studies as well as interventional studies are needed to more clearly understand the complex biology of cardiovascular and kidney disease progression.